A Phase I Trial of Vandetanib (AZD6474) and Selumetinib (AZD6244) for Solid Tumours Including Non Small Cell Lung Cancer (VanSel-1)

Sponsor
Cancer Research UK (Other)
Overall Status
Completed
CT.gov ID
NCT01586624
Collaborator
AstraZeneca (Industry)
61
Enrollment
4
Locations
8
Arms
101
Actual Duration (Months)
15.3
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether using two drugs together called vandetanib and selumetinib is effective in the treatment of cancer. The first part of this study will include patients with any solid tumour and the second part of this study will include only patients with non small cell lung cancer. The four main aims of this clinical study are to find out:

  • If the two drugs can be given safely to patients when given together.

  • The maximum dose that can be given safely to patients.

  • More about the potential side effects of the drugs and how they can be managed.

  • What happens to vandetanib and selumetinib inside the body.

Condition or DiseaseIntervention/TreatmentPhase
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
Phase 1

Detailed Description

The purpose of this Phase I study is to establish a safety and toxicity profile of combining two study drugs; vandetanib, a VEGFR (Vascular Endothelial Growth Factor Receptor) and EGFR (Epidermal Growth Factor Receptor) inhibitor, with selumetinib a MEK (Mitogen Activated Kinase) inhibitor.

This is the first time the drugs have been used together. These types of drugs have shown an effect in non small cell lung cancer (NSCLC).

The study is in two parts; the dose escalation phase and the expansion phase.

In the dose escalation phase, 42-50 patients will receive different doses of vandetanib and increasing doses of selumetinib to establish a safe dose to recommend for the next stage of the study. Patients with any solid tumour will be eligible.

In the expansion phase, up to 30 patients will receive the dose recommended in the previous phase. Only patients with NSCLC will be eligible for this part of the study.

The expansion phase will look at further evaluating the safety of the drug combination and the anti-tumour activity. Patients in this cohort will be requested to also consent to have additional imaging assessments and optional tumour biopsies.

Study treatment is administered orally; vandetanib tablets once daily and selumetinib capsules once daily (OD)/twice daily (BD). Cycle 1 is 42 days long. Subsequent cycles are 28 days in length. Patients will receive a total of 6 cycles of the combination treatment. If the patient has not progressed after six cycles, they may be treated for further cycles following approval from the sponsor.

Study Design

Study Type:
Interventional
Actual Enrollment :
61 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Cancer Research UK Phase I Dose Escalation Trial of Oral VEGFR and EGFR Inhibitor, Vandetanib in Combination With the Oral MEK Inhibitor, Selumetinib (VanSel-1) in Solid Tumours (Dose Escalation) and NSCLC (Expansion Cohort).
Actual Study Start Date :
Jan 10, 2012
Actual Primary Completion Date :
Jun 11, 2020
Actual Study Completion Date :
Jun 11, 2020

Arms and Interventions

ArmIntervention/Treatment
Experimental: Dose Escalation Phase Cohort 1 (Steady state dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Dose Escalation Phase Cohort 2 (Steady state dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Dose Escalation Phase Cohort 3 (Steady state dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Dose Escalation Phase Cohort 4 (Steady state dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Dose Escalation Phase Cohort 5a (Steady state dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Dose Escalation Phase Cohort 5b (Steady state dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Dose Escalation Phase Cohort 6 (Steady state dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Expansion Phase (Steady state dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)

Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Outcome Measures

Primary Outcome Measures

  1. Number of Serious Adverse Events, Non-serious Adverse Events and Treatment Emergent Adverse Events. [Safety data was collected from the date of written informed consent and continued until 28 days after the final administration of vandetanib and selumetinib, an average (mean) of 164 days (approximately 5.4 months).]

    Number of serious adverse events, non-serious adverse events and treatment emergent adverse events.

  2. Number of Dose Limiting Toxicities (DLTs) Within Each Cohort. [DLTs occurring in the first Cycle (up to Day 42).]

    Number of DLTs within each cohort.

Secondary Outcome Measures

  1. Dose Escalation Cohorts Only: PK Parameter Maximum Observed Plasma Concentration of Vandetanib. [0 hours (pre dose) and at 0.5, 2, 4, 6 and 24 hours post dose on Day 4. 0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.]

    Maximum observed plasma concentration of vandetanib post treatment with vandetanib alone and following the combination of vandetanib and selumetinib.

  2. Dose Escalation Cohorts Only: PK Parameter Maximum Observed Plasma Concentration of Selumetinib. [0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.]

    Maximum observed plasma concentration of selumetinib post treatment with the combination of vandetanib and selumetinib.

  3. Dose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-24 Hours) of Vandetanib. [0 hours (pre dose) and at 0.5, 2, 4, 6 and 24 hours post dose on Day 4. 0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.]

    Area under the plasma concentration time curve (0-24 hours) of vandetanib post treatment with vandetanib alone and following the combination of vandetanib and selumetinib.

  4. Dose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-12 Hours) of Selumetinib. [0 hours (pre dose) and at 0.5, 2, 4, 6 and 10 hours post dose on Days 15 and 29.]

    Area under the plasma concentration time curve (0-12 hours) of selumetinib post treatment with the combination of vandetanib and selumetinib. This was extrapolated from the sampling data up to 10 hours to allow comparison with literature data.

  5. Dose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-12 Hours) of N-desmethyl Metabolite of Selumetinib. [0 hours (pre dose) and at 0.5, 2, 4, 6 and 10 hours post dose on Days 15 and 29.]

    Area under the plasma concentration time curve (0-12 hours) of N-desmethyl metabolite of selumetinib following the combination of vandetanib and selumetinib. This was extrapolated from the sampling data up to 10 hours to allow comparison with literature data.

  6. Expansion Cohort Only: Progression Free Survival (PFS) of Patients With NSCLC After Treatment With the Combination of Vandetanib and Selumetinib. [10 and 18 weeks from date of first dose of vandetanib.]

    PFS by Response Evaluation Criteria in Solid Tumours Criteria (RECIST v1.0). Per RECIST for target lesions and assessed by computerised tomography (CT), progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum while on trial, or the appearance of one or more new lesions.

  7. Expansion Cohort Only: One Year Survival of Patients With NSCLC After Treatment With the Combination of Vandetanib and Selumetinib. [1 year from date of first dose of vandetanib.]

    Number of patients alive at one year.

  8. Expansion Cohort Only: Tumour Metabolism in Patients With NSCLC Using Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST) Criteria. [Baseline, Day 12, Day 42.]

    Tumour metabolism using 18F-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) computerised tomography (CT) imaging pre and post treatment with vandetanib alone and following the combination of vandetanib and selumetinib. These were assessed and reported according to PERCIST criteria.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  1. (Dose escalation cohorts) Histologically or cytologically proven solid tumour for which no conventional therapy exists or is declined by the patient

  2. (Expansion cohort only) Histologically or cytologically confirmed NSCLC patients only, for which no conventional therapy exists or is declined by the patient.

  • If only cytologically confirmed, baseline biopsy is mandatory for a patient to be eligible.

  • For NSCLC patients to be eligible for the expansion cohort they must have received:

  • One prior line of chemotherapy and/or

  • Previous platinum based chemotherapy and/or

  • At least one previous EGFR inhibitor

  1. (Expansion cohort only) Measurable disease according to RECIST criteria Version 1.1 in final version of the protocol

  2. Life expectancy of at least 12 weeks

  3. World Health Organisation (WHO) performance status of 0-1

  4. Baseline LVEF > 50%

  5. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day -1) before the patient goes on study.

Laboratory Test Value required

Haemoglobin (Hb) ≥ 9.0 g/dL

Absolute neutrophil count ≥ 1.5 x 10^9/L

Platelet count ≥ 100 x 10^9 /L

Normal serum calcium (adjusted)* 2.15-2.55 mmol/L

Normal serum magnesium* 0.60-1.0 mmol/L

Normal serum potassium >4.0 mmol/L

Either: Serum bilirubin ≥1.5 x upper limit of normal (ULN) This does not apply to patients with Gilbert's disease.

Alanine amino-transferase (ALT) or aspartate amino-transferase (AST) and alkaline phosphatase (ALP) ≤ 2.5 x ULN unless raised due to liver metastases in which case up to 5 x ULN is permissible

Either: Calculated creatinine clearance (using the Wright or C&G formula) > 50 mL/min

Or: Isotope clearance measurement** ≥ 50 mL/min (uncorrected)

INR or aPTT < 1.5 x ULN

*or normal range according to the local laboratory

** Isotope clearance result to be used to confirm eligibility if calculated C&G/Wright method results in GFR of = 50 mL/min.

*** Therapeutic INR values (2.0-3.0) are acceptable to confirm eligibility for patients who are taking concomitant warfarin.

  1. 18 years or over

  2. Ability to swallow and retain oral medications.

  3. Written (signed and dated) informed consent and be capable of co-operating with treatment, and follow-up

Exclusion Criteria:
  1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous 4 weeks (6 weeks for investigational medicinal products) before treatment.

  2. Patients who have been withdrawn from treatment with agents that target EGFR because of unacceptable toxicity (prior treatment with these agents is allowed) and those patients who have had EGFR dose reductions by 50% or more.

  3. Expansion cohort only: Prior treatment with any agent that targets MEK or VEGFR

  4. Any prior exposure to RAS or RAF inhibitors

  5. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 2 toxicities, which in the opinion of the Investigator and the Centre for Drug Development (CDD) should not exclude the patient.

  6. Symptomatic brain metastases (patients must be stable for >3 months post RT treatment) or spinal cord compression.

  7. Patients with interstitial lung disease.

  8. Pregnant or lactating women are excluded. Female patients with the ability to become pregnant who have a negative serum or urine pregnancy test before enrollment and agree to use two of the following three highly effective forms of combined contraception (oral, injected or implanted hormonal contraception and condom, have a intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.

  9. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception [condom plus spermicide] during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (e.g. condom plus spermicidal gel) to prevent exposure to the foetus or neonate.

  10. Major surgery from which the patient has not yet recovered.

  11. At high medical risk because of non-malignant systemic disease including active uncontrolled infection.

  12. Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV).

  13. Cardiac conditions as follows:

  • Clinically significant cardiovascular event within 3 months prior to entry to include:

  • Myocardial infarction

  • Angina requiring use of nitrates more than once weekly

  • Superior vena cava syndrome

  • Class II/III/IV cardiac disease (New York Heart Association [NYHA])

  • Presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia.

  • History of arrhythmia which is symptomatic or requires treatment (CTCAE V4.02), symptomatic or uncontrolled atrial fibrillation despite treatment or asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication are permitted.

  • Uncontrolled hypertension (BP > 160/100 despite optimal therapy)

  • Prior or current cardiomyopathy

  • Atrial fibrillation with heart rate > 100 bpm

  • QTcB > or equal to 450 msec on screening ECG (Note: If a patient has a QTcB interval > or equal to 450 msec on screening ECG, the screen ECG may be repeated twice [at least 24 hours apart]. The average QTcB from the three screening ECGs must be < 450 msec in order for the subject to be eligible for the study.)

  • History of congenital long QT syndrome

  • History of Torsade de Pointes (or any concurrent medication with a known risk of inducing Torsades de Pointes.)

  1. Concomitant medications that are potent inducers of CYP3A4 function i.e. rifampicin, rifabutin, phenytoin, carbamazepine, Phenobarbital and St John"s Wort.

  2. Any other condition which in the Investigator"s opinion would not make the patient a good candidate for the clinical trial (e.g. evidence of severe or uncontrolled systemic disease or concurrent condition or that may affect ability to absorb oral agents).

  3. Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for five years or more and are deemed at negligible risk for recurrence, are eligible for the trial.

  4. If a participant plans to participate in another interventional clinical study, whilst taking part in this Phase I study. Participation in an observational study would be acceptable.

  5. Ophthalmological conditions as follows:

  6. Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein occlusion.

  7. Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma (irrespective of IOP).

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1Churchill HospitalHeadingtonOxfordUnited Kingdom
2Addenbrooke's HospitalCambridgeUnited Kingdom
3The Christie HospitalManchesterUnited Kingdom
4Freeman HospitalNewcastleUnited Kingdom

Sponsors and Collaborators

  • Cancer Research UK
  • AstraZeneca

Investigators

  • Principal Investigator: Denis Talbot, Prof, Oxford University Hospitals NHS Trust

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Cancer Research UK
ClinicalTrials.gov Identifier:
NCT01586624
Other Study ID Numbers:
  • CRUKD/11/001
  • 2011-000627-33
First Posted:
Apr 27, 2012
Last Update Posted:
Oct 7, 2021
Last Verified:
Sep 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Cancer Research UK
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment DetailsTrial participants were enrolled at three trial sites between 10 January 2012 and 19 September 2017.
Pre-assignment Detail
Arm/Group TitleDose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group DescriptionDose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Period Title: Overall Study
STARTED666798811
COMPLETED22101001
NOT COMPLETED445788810

Baseline Characteristics

Arm/Group TitleDose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib )Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib )Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Total
Arm/Group DescriptionDose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Total of all reporting groups
Overall Participants66679881161
Age (Count of Participants)
<=18 years
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Between 18 and 65 years
0
0%
5
83.3%
3
50%
5
71.4%
3
33.3%
3
37.5%
4
50%
6
54.5%
29
47.5%
>=65 years
6
100%
1
16.7%
3
50%
2
28.6%
6
66.7%
5
62.5%
4
50%
5
45.5%
32
52.5%
Sex: Female, Male (Count of Participants)
Female
3
50%
2
33.3%
4
66.7%
4
57.1%
2
22.2%
6
75%
4
50%
6
54.5%
31
50.8%
Male
3
50%
4
66.7%
2
33.3%
3
42.9%
7
77.8%
2
25%
4
50%
5
45.5%
30
49.2%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]
0
0%
Region of Enrollment (participants) [Number]
United Kingdom
6
100%
6
100%
6
100%
7
100%
9
100%
8
100%
8
100%
11
100%
61
100%

Outcome Measures

1. Primary Outcome
TitleNumber of Serious Adverse Events, Non-serious Adverse Events and Treatment Emergent Adverse Events.
DescriptionNumber of serious adverse events, non-serious adverse events and treatment emergent adverse events.
Time FrameSafety data was collected from the date of written informed consent and continued until 28 days after the final administration of vandetanib and selumetinib, an average (mean) of 164 days (approximately 5.4 months).

Outcome Measure Data

Analysis Population Description
All patients who met the eligibility criteria and received at least one dose of the combination treatment (vandetanib and selumetinib) were evaluable for safety assessment (N=57).
Arm/Group TitleDose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group DescriptionDose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants666787611
Total SAEs
10
11
13
5
28
10
14
14
Total NSAEs
99
90
70
94
161
98
114
130
Total treatment emergent AEs
107
99
79
93
165
102
126
135
2. Primary Outcome
TitleNumber of Dose Limiting Toxicities (DLTs) Within Each Cohort.
DescriptionNumber of DLTs within each cohort.
Time FrameDLTs occurring in the first Cycle (up to Day 42).

Outcome Measure Data

Analysis Population Description
All patients who met the eligibility criteria and received at least one dose of the combination treatment (vandetanib and selumetinib) were evaluable for safety assessment (N=57).
Arm/Group TitleDose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group DescriptionDose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants666787611
Number [DLTs]
1
0
1
1
2
1
1
2
3. Secondary Outcome
TitleDose Escalation Cohorts Only: PK Parameter Maximum Observed Plasma Concentration of Vandetanib.
DescriptionMaximum observed plasma concentration of vandetanib post treatment with vandetanib alone and following the combination of vandetanib and selumetinib.
Time Frame0 hours (pre dose) and at 0.5, 2, 4, 6 and 24 hours post dose on Day 4. 0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.

Outcome Measure Data

Analysis Population Description
All patients in the dose escalation cohorts (Cohorts 1 to 6) who received at least one dose of IMP (N=47 with available PK data).
Arm/Group TitleDose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group DescriptionDose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants6667886
Day 4
585
561
582
790
484.5
702.5
702
Day 15
503.5
436
414.5
476
401.5
701
906
Day 29
556
399
538
503
335.5
988
902
4. Secondary Outcome
TitleDose Escalation Cohorts Only: PK Parameter Maximum Observed Plasma Concentration of Selumetinib.
DescriptionMaximum observed plasma concentration of selumetinib post treatment with the combination of vandetanib and selumetinib.
Time Frame0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.

Outcome Measure Data

Analysis Population Description
All patients in the dose escalation cohorts (Cohorts 1 to 6) who received at least one dose of IMP (N=47 with available PK data).
Arm/Group TitleDose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group DescriptionDose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants6667886
Day 15
324.5
605
1280
1890
2005
501
814
Day 29
430
569
1220
1740
1440
587
593
5. Secondary Outcome
TitleDose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-24 Hours) of Vandetanib.
DescriptionArea under the plasma concentration time curve (0-24 hours) of vandetanib post treatment with vandetanib alone and following the combination of vandetanib and selumetinib.
Time Frame0 hours (pre dose) and at 0.5, 2, 4, 6 and 24 hours post dose on Day 4. 0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.

Outcome Measure Data

Analysis Population Description
All patients in the dose escalation cohorts (Cohorts 1 to 6) who received at least one dose of IMP (N=47 with available PK data).
Arm/Group TitleDose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group DescriptionDose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants6667886
Day 4
12032
11629.5
11189
16603
10286.5
14395
14830.5
Day 15
9253.5
8822.5
7958.5
9946
8814.5
15442
18864
Day 29
12555
8355
11246
10058
7261.5
18573
15923
6. Secondary Outcome
TitleDose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-12 Hours) of Selumetinib.
DescriptionArea under the plasma concentration time curve (0-12 hours) of selumetinib post treatment with the combination of vandetanib and selumetinib. This was extrapolated from the sampling data up to 10 hours to allow comparison with literature data.
Time Frame0 hours (pre dose) and at 0.5, 2, 4, 6 and 10 hours post dose on Days 15 and 29.

Outcome Measure Data

Analysis Population Description
All patients in the dose escalation cohorts (Cohorts 1 to 6) who received at least one dose of IMP (N=47 with available PK data).
Arm/Group TitleDose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group DescriptionDose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants6667886
Day 15
1251.5
2050
4072.5
6138
6921
1698
2770
Day 29
1913
2550
4762
6998
6429
3049
2477
7. Secondary Outcome
TitleDose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-12 Hours) of N-desmethyl Metabolite of Selumetinib.
DescriptionArea under the plasma concentration time curve (0-12 hours) of N-desmethyl metabolite of selumetinib following the combination of vandetanib and selumetinib. This was extrapolated from the sampling data up to 10 hours to allow comparison with literature data.
Time Frame0 hours (pre dose) and at 0.5, 2, 4, 6 and 10 hours post dose on Days 15 and 29.

Outcome Measure Data

Analysis Population Description
All patients in the dose escalation cohorts (Cohorts 1 to 6) who received at least one dose of IMP (N=47 with available PK data).
Arm/Group TitleDose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group DescriptionDose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants6667886
Day 15
78.5
141
255
349
493
182
236
Day 29
89
163
230
390
377
293
205
8. Secondary Outcome
TitleExpansion Cohort Only: Progression Free Survival (PFS) of Patients With NSCLC After Treatment With the Combination of Vandetanib and Selumetinib.
DescriptionPFS by Response Evaluation Criteria in Solid Tumours Criteria (RECIST v1.0). Per RECIST for target lesions and assessed by computerised tomography (CT), progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum while on trial, or the appearance of one or more new lesions.
Time Frame10 and 18 weeks from date of first dose of vandetanib.

Outcome Measure Data

Analysis Population Description
All patients in the expansion cohort receiving at least one cycle* of the vandetanib and selumetinib combination with a baseline assessment of disease (N=9). *To be evaluable for response, a patient must have received a minimum of 21 of the 28 daily doses of the combination treatment in Cycle 1.
Arm/Group TitleExpansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group DescriptionExpansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants9
Progression free at 10 weeks
3
50%
Progression free at 18 weeks
2
33.3%
9. Secondary Outcome
TitleExpansion Cohort Only: One Year Survival of Patients With NSCLC After Treatment With the Combination of Vandetanib and Selumetinib.
DescriptionNumber of patients alive at one year.
Time Frame1 year from date of first dose of vandetanib.

Outcome Measure Data

Analysis Population Description
All patients in the expansion cohort receiving at least one cycle* of the vandetanib and selumetinib combination with a baseline assessment of disease (N=9). *To be evaluable for response, a patient must have received a minimum of 21 of the 28 daily doses of the combination treatment in Cycle 1.
Arm/Group TitleExpansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group DescriptionExpansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants9
Number [participants]
2
33.3%
10. Secondary Outcome
TitleExpansion Cohort Only: Tumour Metabolism in Patients With NSCLC Using Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST) Criteria.
DescriptionTumour metabolism using 18F-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) computerised tomography (CT) imaging pre and post treatment with vandetanib alone and following the combination of vandetanib and selumetinib. These were assessed and reported according to PERCIST criteria.
Time FrameBaseline, Day 12, Day 42.

Outcome Measure Data

Analysis Population Description
All patients in the expansion cohort receiving at least one cycle* of the vandetanib and selumetinib combination with a baseline assessment of disease (N=9). *To be evaluable for response, a patient must have received a minimum of 21 of the 28 daily doses of the combination treatment in Cycle 1.
Arm/Group TitleExpansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group DescriptionExpansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants9
Day 12 Complete Metabolic Response
0
0%
Day 12 Partial Metabolic Response
0
0%
Day 12 Stable Metabolic Disease
8
133.3%
Day 12 Progressive Metabolic Disease
1
16.7%
Day 42 Complete Metabolic Response
0
0%
Day 42 Partial Metabolic Response
2
33.3%
Day 42 Stable Metabolic Disease
3
50%
Day 42 Progressive Metabolic Disease
2
33.3%
Day 42 Not assessed
2
33.3%

Adverse Events

Time FrameSafety data was collected from the date of written informed consent and continued until 28 days after the final administration of vandetanib and selumetinib, an average (mean) of 164 days (approximately 5.4 months). Overall Mortality was collected during the Safety data assessment period for the dose Escalation Cohorts and up to one year after Cycle 1 Day 1 for the Expansion Cohort.
Adverse Event Reporting Description Per protocol, where deaths due to disease progression were reported as AEs, these weren't considered to be SAEs unless related to the IMP. These events were coded by the Sponsor as "Death NOS" in the clinical database but have been entered as disease progression at the request of ClinicalTrials.gov. For patients recruited to the expansion cohort, deaths due to disease progression in the survival follow-up period were not reported as AEs but have been included in the All-cause mortality numbers.
Arm/Group TitleDose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)Dose Escalation Phase Cohort 2 ( Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group DescriptionDose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
All Cause Mortality
Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)Dose Escalation Phase Cohort 2 ( Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total0/6 (0%) 1/6 (16.7%) 2/6 (33.3%) 0/7 (0%) 1/8 (12.5%) 0/7 (0%) 1/6 (16.7%) 7/11 (63.6%)
Serious Adverse Events
Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)Dose Escalation Phase Cohort 2 ( Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total4/6 (66.7%) 4/6 (66.7%) 6/6 (100%) 2/7 (28.6%) 7/8 (87.5%) 5/7 (71.4%) 6/6 (100%) 8/11 (72.7%)
Cardiac disorders
Cardiac disorders - Other, specify0/6 (0%) 1/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Paroxysmal atrial tachycardia0/6 (0%) 0/6 (0%) 1/6 (16.7%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Sinus bradycardia0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Pericardial effusion0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Eye disorders
Eye disorders - Other, specify0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 2/6 (33.3%) 21/11 (9.1%) 1
Retinal detachment0/6 (0%) 0/6 (0%) 2/6 (33.3%) 20/7 (0%) 23/8 (37.5%) 41/7 (14.3%) 13/6 (50%) 31/11 (9.1%) 1
Retinal vascular disorder0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 10/11 (0%) 1
Retinopathy0/6 (0%) 0/6 (0%) 1/6 (16.7%) 10/7 (0%) 11/8 (12.5%) 11/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Gastrointestinal disorders
Abdominal pain0/6 (0%) 1/6 (16.7%) 11/6 (16.7%) 10/7 (0%) 11/8 (12.5%) 30/7 (0%) 30/6 (0%) 30/11 (0%) 3
Diarrhea2/6 (33.3%) 22/6 (33.3%) 21/6 (16.7%) 10/7 (0%) 12/8 (25%) 80/7 (0%) 81/6 (16.7%) 23/11 (27.3%) 3
Dysphagia0/6 (0%) 1/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Gastrointestinal disorders - Other, specify0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 10/8 (0%) 10/7 (0%) 11/6 (16.7%) 10/11 (0%) 1
Nausea1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Obstruction gastric0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Vomiting1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 11/8 (12.5%) 40/7 (0%) 40/6 (0%) 41/11 (9.1%) 1
General disorders
Disease Progression0/6 (0%) 1/6 (16.7%) 11/6 (16.7%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Fever0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Infections and infestations
Biliary tract infection0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 11/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Infections and infestations - Other, specify0/6 (0%) 1/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 11/7 (14.3%) 10/6 (0%) 11/11 (9.1%) 1
Lung infection0/6 (0%) 1/6 (16.7%) 11/6 (16.7%) 10/7 (0%) 11/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Urinary tract infection0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 10/11 (0%) 1
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications - Other, specify0/6 (0%) 1/6 (16.7%) 11/6 (16.7%) 10/7 (0%) 10/8 (0%) 11/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Metabolism and nutrition disorders
Dehydration1/6 (16.7%) 20/6 (0%) 20/6 (0%) 20/7 (0%) 20/8 (0%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2
Hypercalcemia0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Hyponatremia0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Musculoskeletal and connective tissue disorders
Muscle weakness lower limb0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Pain in extremity0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Nervous system disorders
Stroke1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Ischemia cerebrovascular0/6 (0%) 1/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Presyncope0/6 (0%) 0/6 (0%) 2/6 (33.3%) 20/7 (0%) 20/8 (0%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2
Renal and urinary disorders
Acute kidney injury1/6 (16.7%) 11/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 12/11 (18.2%) 2
Urine discoloration0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Urinary retention0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Respiratory, thoracic and mediastinal disorders
Bronchopleural fistula0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Dyspnea1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 11/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Hypoxia0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Laryngeal hemorrhage0/6 (0%) 0/6 (0%) 1/6 (16.7%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Respiratory, thoracic and mediastinal disorders - Other, specify1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Skin and subcutaneous tissue disorders
Erythroderma0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 10/11 (0%) 1
Rash acneiform0/6 (0%) 0/6 (0%) 1/6 (16.7%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 13/6 (50%) 30/11 (0%) 3
Rash maculo-papular0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 2/8 (25%) 20/7 (0%) 20/6 (0%) 23/11 (27.3%) 3
Vascular disorders
Thromboembolic event0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Other (Not Including Serious) Adverse Events
Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)Dose Escalation Phase Cohort 2 ( Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total6/6 (100%) 6/6 (100%) 6/6 (100%) 7/7 (100%) 8/8 (100%) 7/7 (100%) 6/6 (100%) 11/11 (100%)
Blood and lymphatic system disorders
Anaemia0/6 (0%) 1/6 (16.7%) 10/6 (0%) 11/7 (14.3%) 10/8 (0%) 11/7 (14.3%) 11/6 (16.7%) 10/11 (0%) 1
Cardiac disorders
Chest pain - cardiac1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Cardiac disorders - Other, specify0/6 (0%) 0/6 (0%) 1/6 (16.7%) 10/7 (0%) 11/8 (12.5%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2
Palpitations0/6 (0%) 0/6 (0%) 1/6 (16.7%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Atrial fibrillation0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Sinus bradycardia0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Sinus tachycardia1/6 (16.7%) 11/6 (16.7%) 10/6 (0%) 10/7 (0%) 12/8 (25%) 20/7 (0%) 20/6 (0%) 21/11 (9.1%) 1
Ear and labyrinth disorders
Hearing impaired1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Ear and labyrinth disorders - Other, specify0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 10/11 (0%) 1
Eye disorders
Blurred vision2/6 (33.3%) 20/6 (0%) 21/6 (16.7%) 10/7 (0%) 11/8 (12.5%) 11/7 (14.3%) 11/6 (16.7%) 21/11 (9.1%) 1
Eye disorders - Other, specify0/6 (0%) 0/6 (0%) 0/6 (0%) 2/7 (28.6%) 20/8 (0%) 21/7 (14.3%) 10/6 (0%) 11/11 (9.1%) 1
Eyelid function disorder0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Flashing lights0/6 (0%) 1/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Floaters0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Glaucoma0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Gastrointestinal disorders
Abdominal distension0/6 (0%) 1/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Abdominal pain3/6 (50%) 30/6 (0%) 30/6 (0%) 31/7 (14.3%) 33/8 (37.5%) 63/7 (42.9%) 32/6 (33.3%) 20/11 (0%) 2
Bloating0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Colitis0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Constipation2/6 (33.3%) 33/6 (50%) 31/6 (16.7%) 12/7 (28.6%) 32/8 (25%) 32/7 (28.6%) 20/6 (0%) 21/11 (9.1%) 1
Diarrhea5/6 (83.3%) 75/6 (83.3%) 125/6 (83.3%) 64/7 (57.1%) 65/8 (62.5%) 177/7 (100%) 175/6 (83.3%) 148/11 (72.7%) 16
Dry mouth1/6 (16.7%) 11/6 (16.7%) 21/6 (16.7%) 11/7 (14.3%) 10/8 (0%) 11/7 (14.3%) 10/6 (0%) 11/11 (9.1%) 1
Dyspepsia0/6 (0%) 0/6 (0%) 1/6 (16.7%) 11/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Esophageal hemorrhage0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Flatulence1/6 (16.7%) 11/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Gastroesophageal reflux disease0/6 (0%) 0/6 (0%) 1/6 (16.7%) 10/7 (0%) 11/8 (12.5%) 30/7 (0%) 30/6 (0%) 30/11 (0%) 3
Gastrointestinal disorders - Other, specify1/6 (16.7%) 10/6 (0%) 10/6 (0%) 11/7 (14.3%) 30/8 (0%) 30/7 (0%) 30/6 (0%) 30/11 (0%) 3
Malabsorption0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Mucositis oral1/6 (16.7%) 12/6 (33.3%) 31/6 (16.7%) 12/7 (28.6%) 20/8 (0%) 21/7 (14.3%) 12/6 (33.3%) 32/11 (18.2%) 2
Nausea4/6 (66.7%) 53/6 (50%) 63/6 (50%) 55/7 (71.4%) 94/8 (50%) 84/7 (57.1%) 83/6 (50%) 64/11 (36.4%) 8
Oral hemorrhage0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 2
Oral pain0/6 (0%) 0/6 (0%) 2/6 (33.3%) 20/7 (0%) 20/8 (0%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2
Rectal hemorrhage0/6 (0%) 1/6 (16.7%) 20/6 (0%) 20/7 (0%) 21/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Stomach pain0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 10/8 (0%) 10/7 (0%) 11/6 (16.7%) 10/11 (0%) 1
Vomiting4/6 (66.7%) 52/6 (33.3%) 43/6 (50%) 45/7 (71.4%) 101/8 (12.5%) 44/7 (57.1%) 102/6 (33.3%) 42/11 (18.2%) 4
General disorders
Chills0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Disease Progression0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 2/11 (18.2%) 2
Edema limbs1/6 (16.7%) 11/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 11/7 (14.3%) 10/6 (0%) 11/11 (9.1%) 1
Fatigue3/6 (50%) 45/6 (83.3%) 55/6 (83.3%) 73/7 (42.9%) 43/8 (37.5%) 32/7 (28.6%) 22/6 (33.3%) 26/11 (54.5%) 10
Fever0/6 (0%) 0/6 (0%) 1/6 (16.7%) 10/7 (0%) 11/8 (12.5%) 11/7 (14.3%) 11/6 (16.7%) 10/11 (0%) 1
Flu like symptoms1/6 (16.7%) 20/6 (0%) 21/6 (16.7%) 10/7 (0%) 11/8 (12.5%) 11/7 (14.3%) 10/6 (0%) 11/11 (9.1%) 1
General disorders and administration site conditions - Other, specify1/6 (16.7%) 11/6 (16.7%) 10/6 (0%) 10/7 (0%) 11/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Non-cardiac chest pain2/6 (33.3%) 21/6 (16.7%) 10/6 (0%) 11/7 (14.3%) 12/8 (25%) 21/7 (14.3%) 11/6 (16.7%) 12/11 (18.2%) 2
Pain0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Hepatobiliary disorders
Hepatic pain0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2
Immune system disorders
Allergic reaction0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 10/11 (0%) 1
Infections and infestations
Infections and infestations - Other, specify3/6 (50%) 30/6 (0%) 32/6 (33.3%) 31/7 (14.3%) 13/8 (37.5%) 41/7 (14.3%) 20/6 (0%) 22/11 (18.2%) 4
Lung infection0/6 (0%) 0/6 (0%) 1/6 (16.7%) 10/7 (0%) 11/8 (12.5%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2
Nail infection0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 2
Papulopustular rash0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Paronychia0/6 (0%) 1/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 12/11 (18.2%) 2
Skin infection0/6 (0%) 1/6 (16.7%) 11/6 (16.7%) 12/7 (28.6%) 30/8 (0%) 30/7 (0%) 30/6 (0%) 30/11 (0%) 3
Tooth infection0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Upper respiratory infection1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 11/8 (12.5%) 11/7 (14.3%) 12/6 (33.3%) 22/11 (18.2%) 2
Urinary tract infection2/6 (33.3%) 20/6 (0%) 20/6 (0%) 21/7 (14.3%) 11/8 (12.5%) 11/7 (14.3%) 12/6 (33.3%) 30/11 (0%) 3
Vaginal infection1/6 (16.7%) 11/6 (16.7%) 11/6 (16.7%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications - Other, specify1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 11/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Fall0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Investigations
Activated partial thromboplastin time prolonged0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 2/6 (33.3%) 30/11 (0%) 3
Alanine aminotransferase increased0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 11/8 (12.5%) 12/7 (28.6%) 24/6 (66.7%) 42/11 (18.2%) 2
Alkaline phosphatase increased0/6 (0%) 1/6 (16.7%) 10/6 (0%) 10/7 (0%) 11/8 (12.5%) 11/7 (14.3%) 11/6 (16.7%) 11/11 (9.1%) 1
Aspartate aminotransferase increased1/6 (16.7%) 10/6 (0%) 12/6 (33.3%) 20/7 (0%) 22/8 (25%) 22/7 (28.6%) 24/6 (66.7%) 52/11 (18.2%) 2
Blood bilirubin increased0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 11/11 (9.1%) 2
Cardiac troponin I increased0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 10/11 (0%) 1
Cholesterol high0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
CPK increased0/6 (0%) 1/6 (16.7%) 12/6 (33.3%) 20/7 (0%) 22/8 (25%) 30/7 (0%) 33/6 (50%) 74/11 (36.4%) 6
Creatinine increased0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 2/6 (33.3%) 22/11 (18.2%) 2
Ejection fraction decreased0/6 (0%) 1/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 11/6 (16.7%) 10/11 (0%) 1
Electrocardiogram QT corrected interval prolonged2/6 (33.3%) 20/6 (0%) 20/6 (0%) 20/7 (0%) 23/8 (37.5%) 32/7 (28.6%) 24/6 (66.7%) 70/11 (0%) 7
Investigations - Other, specify0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Neutrophil count decreased0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 10/11 (0%) 1
Platelet count decreased0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 2/6 (33.3%) 60/11 (0%) 6
Weight loss1/6 (16.7%) 11/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 11/6 (16.7%) 11/11 (9.1%) 1
Metabolism and nutrition disorders
Anorexia4/6 (66.7%) 41/6 (16.7%) 11/6 (16.7%) 11/7 (14.3%) 13/8 (37.5%) 33/7 (42.9%) 30/6 (0%) 30/11 (0%) 3
Hypercalcemia0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 11/8 (12.5%) 10/7 (0%) 11/6 (16.7%) 10/11 (0%) 1
Hyperkalemia1/6 (16.7%) 11/6 (16.7%) 20/6 (0%) 23/7 (42.9%) 60/8 (0%) 61/7 (14.3%) 11/6 (16.7%) 10/11 (0%) 1
Hypermagnesemia0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Hypertriglyceridemia0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Hypoalbuminemia0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 11/11 (9.1%) 2
Hypocalcemia0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 2/8 (25%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2
Hypoglycemia0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 11/11 (9.1%) 1
Hypokalemia0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 11/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Hypomagnesemia0/6 (0%) 1/6 (16.7%) 11/6 (16.7%) 10/7 (0%) 12/8 (25%) 61/7 (14.3%) 11/6 (16.7%) 11/11 (9.1%) 1
Hyponatremia0/6 (0%) 0/6 (0%) 1/6 (16.7%) 20/7 (0%) 20/8 (0%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2
Musculoskeletal and connective tissue disorders
Arthralgia0/6 (0%) 2/6 (33.3%) 21/6 (16.7%) 10/7 (0%) 14/8 (50%) 71/7 (14.3%) 10/6 (0%) 11/11 (9.1%) 1
Back pain1/6 (16.7%) 11/6 (16.7%) 10/6 (0%) 10/7 (0%) 12/8 (25%) 52/7 (28.6%) 20/6 (0%) 21/11 (9.1%) 1
Bone pain1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Buttock pain0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Chest wall pain1/6 (16.7%) 11/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 11/6 (16.7%) 10/11 (0%) 1
Muscle weakness lower limb0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 11/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Muscle weakness upper limb0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Musculoskeletal and connective tissue disorder - Other, specify0/6 (0%) 0/6 (0%) 1/6 (16.7%) 10/7 (0%) 11/8 (12.5%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2
Myalgia0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Myositis0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Neck pain1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 11/8 (12.5%) 30/7 (0%) 30/6 (0%) 30/11 (0%) 3
Pain in extremity0/6 (0%) 1/6 (16.7%) 20/6 (0%) 21/7 (14.3%) 11/8 (12.5%) 30/7 (0%) 31/6 (16.7%) 10/11 (0%) 1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Nervous system disorders
Amnesia1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Cognitive disturbance0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Dizziness1/6 (16.7%) 10/6 (0%) 10/6 (0%) 11/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Dysgeusia0/6 (0%) 1/6 (16.7%) 11/6 (16.7%) 11/7 (14.3%) 10/8 (0%) 11/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Extrapyramidal disorder0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 10/11 (0%) 1
Headache2/6 (33.3%) 41/6 (16.7%) 12/6 (33.3%) 21/7 (14.3%) 10/8 (0%) 11/7 (14.3%) 20/6 (0%) 21/11 (9.1%) 1
Lethargy1/6 (16.7%) 10/6 (0%) 11/6 (16.7%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Memory impairment0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Nervous system disorders - Other, specify1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Neuralgia0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Peripheral sensory neuropathy0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 11/6 (16.7%) 20/11 (0%) 2
Presyncope0/6 (0%) 1/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Somnolence0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Syncope1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Psychiatric disorders
Anxiety0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Confusion0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Depression1/6 (16.7%) 10/6 (0%) 10/6 (0%) 11/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 11/11 (9.1%) 1
Insomnia1/6 (16.7%) 11/6 (16.7%) 10/6 (0%) 10/7 (0%) 13/8 (37.5%) 40/7 (0%) 40/6 (0%) 40/11 (0%) 4
Libido increased0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Renal and urinary disorders
Cystitis noninfective1/6 (16.7%) 20/6 (0%) 20/6 (0%) 20/7 (0%) 20/8 (0%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2
Urinary frequency0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Urinary incontinence0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 2/7 (28.6%) 20/6 (0%) 20/11 (0%) 2
Urinary urgency0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2
Reproductive system and breast disorders
Vaginal inflammation1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Pelvic pain0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2
Respiratory, thoracic and mediastinal disorders
Cough2/6 (33.3%) 20/6 (0%) 22/6 (33.3%) 20/7 (0%) 22/8 (25%) 22/7 (28.6%) 21/6 (16.7%) 15/11 (45.5%) 6
Dyspnea2/6 (33.3%) 22/6 (33.3%) 21/6 (16.7%) 11/7 (14.3%) 13/8 (37.5%) 31/7 (14.3%) 11/6 (16.7%) 12/11 (18.2%) 2
Epistaxis0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 11/8 (12.5%) 10/7 (0%) 12/6 (33.3%) 21/11 (9.1%) 1
Hoarseness0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 2/6 (33.3%) 20/11 (0%) 2
Hypoxia1/6 (16.7%) 10/6 (0%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 11/11 (9.1%) 1
Laryngospasm0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 10/11 (0%) 1
Nasal congestion0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Productive cough0/6 (0%) 1/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 11/11 (9.1%) 1
Respiratory, thoracic and mediastinal disorders - Other, specify0/6 (0%) 1/6 (16.7%) 20/6 (0%) 20/7 (0%) 20/8 (0%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2
Sore throat0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 11/8 (12.5%) 11/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Wheezing0/6 (0%) 0/6 (0%) 1/6 (16.7%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Skin and subcutaneous tissue disorders
Alopecia0/6 (0%) 1/6 (16.7%) 10/6 (0%) 11/7 (14.3%) 11/8 (12.5%) 11/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Dry skin2/6 (33.3%) 21/6 (16.7%) 12/6 (33.3%) 32/7 (28.6%) 21/8 (12.5%) 10/7 (0%) 11/6 (16.7%) 11/11 (9.1%) 1
Erythema multiforme1/6 (16.7%) 10/6 (0%) 10/6 (0%) 11/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Hyperhidrosis0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 21/7 (14.3%) 10/6 (0%) 10/11 (0%) 1
Nail loss0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Pain of skin0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 10/8 (0%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Palmar-plantar erythrodysesthesia syndrome0/6 (0%) 0/6 (0%) 1/6 (16.7%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 11/6 (16.7%) 11/11 (9.1%) 1
Periorbital edema0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 10/11 (0%) 1
Photosensitivity0/6 (0%) 1/6 (16.7%) 10/6 (0%) 10/7 (0%) 10/8 (0%) 11/7 (14.3%) 12/6 (33.3%) 20/11 (0%) 2
Pruritus1/6 (16.7%) 11/6 (16.7%) 20/6 (0%) 23/7 (42.9%) 40/8 (0%) 40/7 (0%) 41/6 (16.7%) 11/11 (9.1%) 1
Purpura0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 11/8 (12.5%) 20/7 (0%) 20/6 (0%) 21/11 (9.1%) 1
Rash acneiform2/6 (33.3%) 23/6 (50%) 30/6 (0%) 31/7 (14.3%) 11/8 (12.5%) 13/7 (42.9%) 52/6 (33.3%) 31/11 (9.1%) 2
Rash maculo-papular5/6 (83.3%) 73/6 (50%) 32/6 (33.3%) 44/7 (57.1%) 45/8 (62.5%) 73/7 (42.9%) 40/6 (0%) 47/11 (63.6%) 8
Skin and subcutaneous tissue disorders - Other, specify1/6 (16.7%) 13/6 (50%) 52/6 (33.3%) 21/7 (14.3%) 11/8 (12.5%) 10/7 (0%) 10/6 (0%) 11/11 (9.1%) 1
Skin ulceration0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 11/11 (9.1%) 1
Vascular disorders
Flushing0/6 (0%) 1/6 (16.7%) 11/6 (16.7%) 10/7 (0%) 10/8 (0%) 10/7 (0%) 11/6 (16.7%) 11/11 (9.1%) 1
Hot flashes0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 10/7 (0%) 10/6 (0%) 10/11 (0%) 1
Hypertension1/6 (16.7%) 22/6 (33.3%) 21/6 (16.7%) 11/7 (14.3%) 21/8 (12.5%) 13/7 (42.9%) 43/6 (50%) 45/11 (45.5%) 5
Thromboembolic event0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 2/8 (25%) 20/7 (0%) 20/6 (0%) 20/11 (0%) 2

Limitations/Caveats

61 patients were enrolled. 3 withdrew before having vandetanib (Van) or selumetinib (Sel). 1 patient in Cohort 5b received Van but withdrew before having Sel and was excluded from the safety analysis. The remaining 57 patients had at least 1 dose of the combination and were included in the safety analysis population (46 in dose escalation, 11 in expansion). PFS was planned to be assessed at 12 weeks but was instead assessed at 10 and 18 weeks as disease assessments were performed every 2 cycles

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/TitleRegulatory Affairs Manager
OrganizationCancer Research UK Centre for Drug Development
Phone+44 203 4696878
Emailregulatory@cancer.org.uk
Responsible Party:
Cancer Research UK
ClinicalTrials.gov Identifier:
NCT01586624
Other Study ID Numbers:
  • CRUKD/11/001
  • 2011-000627-33
First Posted:
Apr 27, 2012
Last Update Posted:
Oct 7, 2021
Last Verified:
Sep 1, 2021